Note: Descriptions are shown in the official language in which they were submitted.
16 39(2)
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A process for the pre~aration of 2-~2-~4--~(4-chlorophenyl)phenylmethyll-
l-piperazinyl]ethoxyl-acetic acid and lts dihy~_ochloride.
The present invention relates to a new process for the preparation
of 2-[2-[4-[(4-chlorophenyl)phenylmethyl3-1-piperazinyl]ethoxy]-acetic
acid and its dihydrochloride.
The dihydrochloride of 2-[2--[4-[(4-chlorophenyl)phenylmethyl]-1-
piperazinyl]ethoxy]-acetic acid also known by the generic name of
cetirizine, has recently been introduced as a new medicament for the
treatment of allergic syndromes, such as chronic and acute allergic
rhinitis, allergic conjunctivitis, pruritus, urticaria etc. When used in
therapy, this product has proved to be remarkably free from side effects
on the central nervous system, such as drowsiness, reduced mentai
performance etc.(c.f. D.P.TASHKIN et al., Annals of Allergy, Part II, 59,
(1987),49-52, and F.M. GENG0 et al., Annals of Allergy, Part II, 59,
t1987),53_57).
European Patent No.58,146 in the name of the Applicant describes the
15 synthesis of 2-[2-[4-[(4-chlorophenyl)phenylmethyl~-1-
piperazinyl]ethoxy]-acetic acid and its dihydrochloride. In this
synthesis, the starting substance is l-[(4-chlorophenyl)phenylmethyl]-
piperazine, which is reacted with methyl (2-chloroethoxy)-acetate to give
methyl 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-
acetate in a yield of 27.8Z. This methyl ester is then subjected to
hydrolysis with an inorganic base (potassium or sodium hydro~ide) to give
the sodium or potassium salt, which is easily converted into the free
acid, and then into cetirizine dihydrochloride.
The major disadvantage of this synthesis is that the overall yield
25 of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic
acid dihydrochloride is only 10.6%, based on the amount of 1-[(4-
chlorophenyl)phenylmethyl]-piperazine employed.
According to the present invention, a new process for the synthesis
is provided, which enables 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-
piperazinyl]ethoxyj-acetic acid and its dihydrochloride to be prepared
with better yields.
According to the present invention, 2-[2-[4-[(4-chlorophenyl)
' '~ ''' ~
.~
~3~3~
phenylmethy~ -piperazinyl~ethoxy]-acetic acid and its
dihydrochloride are prepared by a process wherein an alkali
metal alcoholate and an alkali metal haloacetate are
alternately and repeatedly added to a reaction medium
comprising 2-[4~[~4-chlorophenyl)phenylmethyl]-1-
piperazinyl]-ethanol, so that the latter reacts with the
alkali metal haloacetate, in the presence of the alkali
metal alcoholate, to form an alkali metal salt o~ the
subject acid and said alkali metal salt is converted either
into the subject acid or into its dihydrochloride.
7 3 2
The 2-[4-[(4-chlorophenyl)phenylmethyl-1-piperazinyl)-ethanol used
as the starting substance in the process oE the invention is a product
which is known per se. Its synthesis by reaction of 1-piperazineethanol
with (4-chlorophenyl)phenylmethyl chloride has already been described in
U.S. Patent No.2,899,436. This product can also be prepared in a higher
yield (9OZ) by reaction of 1-[~4-chlorophenyl)phenylmethyl~-piperazine
with a 2-haloethanol in the presence of an acid acceptor, such as an
inorganic base (for example sodium or potassium carbonate) or a tertiary
organic base (for example triethylamine), in an inert solvent, such as
toluene, xylene or another aromatic solvent.
In accordance with the invention, 2-[2-[4-[(4-
chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic acid is obtained
by reaction of 2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethanol
and an alkali metal haloacetate, such as sodium chloroacetate. This
reaction is generally carried out by heating at between 60 and 100C for
several hours in the presence of an alkali metal alcoholate, such as, for
example, potassium tert-butoxide, and in an organic solvent, preferably
an aliphatic alcohol of low reactivity, such as, for example, tert-
butanol.
To achieve optimum yields, its is advisable to use potassium tert-
butoxide and tert-butanol and to resupply the reaction medium regularly
with the two reactants (alkali metal alcoholate and alkali metal
haloacetate) in smaller and smaller amounts and-at regular intervals
until the reaction is as complete as possible.
By way of example, each reactant can be added to the reaction
mixture every half hour for a total duration of four hours. Each of the
total molar amounts of alcoholate and haloacetate used is advantageously
25 to 75~ higher than the molar amount oE the starting 2-[4-[(4-
chlorophenyl)phenylmethyl]-1-piperazinyl]-ethanol.
For reasons of economy, it is of interest to recover and recycle
the starting alcohol. To this effect, the solvent is removed from the
reaction medium, the latter is taken up in acidified water (to bring the
pH to a weakly basic value) and ~he starting alcohol is extracted with
diethyl ether. The 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-
piperazinyl]ethoxy]-acetic acid which is formed in the course of the
7 ~ .~
reaction i9 present in the reaction mixture ln the form oE an alkali
metal salt. After the reaction mixture is acidiEied to pH 5 by addition
of an inorganic acid (such as hydrochloric acid), the corresponding acid
can be recovered from the reaction mixture by extraction by means of an
organic solvent (dichloromethane, toluene etc.). The desired acid can
also be isolated in the form of well-crystallized salts. This acid can be
converted into the corresponding dihydrochloride of the acid by a
conventional process.
This new synthesis process gives yields of 44% or more of
cetirizine dihydrochloride, calculated on the basis of the 1-[(4-
chlorophenyl)phenylmethyl]-l-piperazine employed. With recycling of the
2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethanol in the
reaction, the overall yield can even reach values close to 50~. This
higher yield starting from 1-[(4-chlorophenyl)phenylmethyl]-1-piperazine
constitutes a considerable technical advance with respect to the process
described in European Patent No.58,146.
The following example is given fo} the purpose of illustrating the
invention.
Example. Preparation of 2-~Z- r 4-~(4-chlorophenyl)~henYlme_hyl~
piperazinyll hoxyl-acetic acid.
1. 2-~4-~4-chlorophenyl)~henylmethyll-1-piperaæinyll-ethanol.
325 ml of dry toluene, 131.2 g (0.458 mole) of 1-[(4-
chlorophenyl)phenylmethyl]-piperazine and 125 ml (0.9 mole) of
triethylamine are introduced successively into a three-necked round-
bottomed flask of 2 litres capacity equipped with a mechanical
stirrer, a condenser and a -thermometer. 41.5 g (0.516 mole) of 2-
chloroethanol are added to this solution and the mixture is brought
to the reflux temperature, while stirring. After heating for six
hours, a further 20 g (0.248 mole~ of 2-chloroethanol are added and
reflux is maintained for an additional six hours.
The reaction mixture is cooled and filtered and the filtrate is
concentrated under a vacuum on a rotary evaporator. 146.5 g of 2-[4-
[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethanol are thus
isolated in the form of a yellow oil in a yield of 96.8%.
50 g of the alcohol obtained are distilled at 220C under reduced
pressure (0.0065 mbar) and collected in two separate fractions.
The purity of each fraction is measured by high pressure liquid
chromatography. One fractlon of 24.5 g has a purity of 96.6%,
~ s~
whereas the other fraction (of 22.2 g) has a purity of 99.6~. A
yield of pure product of 90.4% is thus obtained.
The alcohol thus obtained can be characterized in the form of its
dihydrochloride prepared from an ethanolic solution of gaseous
hydrochloric acid.
M.P.: 222C
Analysis for Cl9H23ClN2 ZHCl in %
calc : C 56.50 H 6.19 N 6.94 Cl 17.59 Cl 26.39
found: C 56.63 H 6.28 N 6.86 Cl 17.48 Cl 26.32
2. 2-~2-~4-~(4-chlorophenyl)phenylmethyll-1-piperazinyllethoxyl-acetic
acid.
50 g (0.15 mole) of 2-~4-[(4-chlorophenyl)phenylmethyl]-1-
piperazinyl]-ethanol and 225 ml of tert-butanol are introduced into
a three-necked round bottomed flask equipped with a mechanical
stirrer, a thermometer, a nitrogen inlet and a condenser. The
mixture is stirred gently and heated to 45C under a nitrogen
atmosphere, and 21 g of potassium tert-butoxide are added. The
temperature is raised to 75-80C and the mixture is kept at this
temperature. ll g of sodium chloroacetate are then added to the
mixture, taking the time of this addition as time zero. Sodium
chloroacetate and potassium tert-butoxide are introduced
successively into the reaction mixture, the temperature being kept
at 75-80C and while stirring under a nitrogen atmosphere, in the
following manner: after 45 minutes 11 g of sodium chloroacetate are
added after 1 hour and a half 5.2 g of potassium tert-butoxide are
added; after 2 hours 5.64 g of sodium chloroacetate are added;
after 2 and a half hours 1.9 g of potassium tert-butoxide are added;
after 3 hours 1.9 g of sodium chloroacetate are added; after 3 and
a half hours 0.8 g of potassium tert-bu-~oxide is added; after 4
hours the operation is ended by addition of 1.13 g of sodium
chloroacetate. A total of 28.92 g (0.25 mole) of potassium tert-
butoxide (97%) and 30.65 g (0.25 mole) of sodium chloroacetate (95%)
has thus been added. The reactor is then converted into a
distillation apparatus and about 150 ml of tert-butanol are
distilled off; 190 ml of water are then added to the reaction
mixture and the distillation of tert-butanol in the form of an
azeotrope with water is continued until the temperature of the
vapours reac:hes 100C.
~ 32~'~3~
The reaction mixture is cooled, diluted with 60 ml of water and
brought to pH 8 by addition of about 8 ml concentrated hydrochloric
acid. The starting 2-[4-[(4-chlorophenyl)phenylmethyl]-1-
piperazinyl]-ethanol which has not reacted is then carefully
extracted with diethyl ether, which enables 7.3 g to be recovered
after evaporation of the solvent.
The aqueous phase, which contains the sodium salt of the desired
acid, is acidified to pH 5 by addition of hydrochloric acid and
extracted three times with 200 ml of dichloromethane. The organic
phases of the extraction are comb:ined and dried over magnesium
sulphate, filtered and concentrated in a rotary evaporator. An oil
is obtained and is allowed to crystallize by addition of 150 ml of
2-butanone, while hot. The solid formed is filtered off and dried.
32.7 g of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-
piperazinyl]ethoxy]-acid are thus isolated.
Yield: 55.5%. M.P.:146-148C.
Y 21 25 lN2O3 in %
calc.: C 64.86 H 6.48 N 7.20 Cl 9.12
found: C 64.67 H 6.46 N 7.19 Cl 9.39
A second crop of product can be obtained by concentration of the
mother liquors (7.4 g).
3. 2-r2-~4-~(4-chlorophenyl)phenylmethyll-1-piperazinyllethoxyl-acetic
acid dihydrochloride.
32.7 g of 2-[2-[4-[(4-chlorophenyl)phenylmethylJ-l-
piperazinyl]ethoxy]-acetic acid are suspended in a mixture of 125 ml
of water and 13.8 ml of 37% aqueous hydrochloric acid. This mixture
is concentrated on a rotary evaporator. An oil is obtained and is
crystallized by addition of 245 ml of 2-butanone. The crystals
formed are filtered off, drained and dried. 34.2 g of 2-[2-[4-[(4-
chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]-acetic acid
dihydrochloride are obtained.
Yield: 88%. M.P.: 228.22C (Differential Scanning Calorimetry, DSC)
Y 21 25 2 3.2HCl in %
calc.: C 54.56 H 5.84 N 6.06 Cl 15.37 Cl 23.05
found: C 54.28 H 5.86 N 6.15 Cl 15.24 Cl 23.22
A second crop of dihydrochloride can be obtained in the same way
starting from the second crop of product obtained above under point
2 (4.5 g).
Taking into account the fact that the 2-[4-[(4-
chlorophenyl)phenylmethyl]-l-piperazinyl]-ethanol ls obtained in a
yield of 90.4Z from l-[(4-chlorophenyl)phenylmethyl]-piperazine, the
2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyllethoxy]-acetic
acid dihydrochloride is thus obtained in three steps in an overall
yield of 44.1~ (or more than 48~ if possible recycling of 2-[4-[(4-
chlorophenyl)phenylmethyl]-l-piperazinyl]-ethanol which has not
reacted is taken into account), which constitutes a marked
improvement with respect to the process according to European
Patent No. 58,146.
